Understanding how the immune system breaks down tolerance to self is critical to controlling and, indeed, reversing autoimmune diseases like type 1 diabetes, multiple sclerosis, and lupus. This meeting will bring together experts in basic immunology and clinical science, as well as the biotech world, to present the latest data and prospects for treatment of these debilitating diseases. Self versus non-self discrimination is one of the basic tenets of immunology. The pathways by which tolerance is established are complex but recent work has provided greater insight into this important process. Understanding how tolerance is induced and "broken" is critical to developing future therapies for a variety of autoimmune disorders, such as diabetes and multiple sclerosis. Novel approaches need to be developed for the treatment of the autoimmune disorders that lead to tissue target cell destruction. This Keystone meeting is centered at understanding tolerance and its breakdown, and bridging the gap between basic, pre-clinical and clinical studies. While there will be an emphasis on basic studies, disease models for dissecting pathogenesis and examining novel therapies in a variety of autoimmune diseases (e.g., diabetes, multiple sclerosis, IBD, uveitis, as well as hemophilia), which will provide a major focus. Thus, a major theme will be the underlying tolerance pathways, as well as how they are subverted. The establishment of new models and therapies, including human clinical trials, will be included. Sessions to be covered include studies of the genes and signals involved in tolerance and autoimmunity, the interaction of the innate and adaptive immune systems, novel approaches for tolerance induction in autoimmune, models, and translation of these to human clinical trials. Proof of principle studies and new biotechnology approaches will also be emphasized. The goals of the meeting are: To provide an understanding of the mechanisms of immune tolerance and its breakdown;To update the audience on autoimmune models and clinical trials; To stimulate interactions between basic and clinical scientists, as well as R & D scientists in industry; from around the globe to collaborate to respond to the challenges in this area; A novel feature this year is the addition of a formal debate session in the evening of the second day, as well as the presentation of the Lifetime Achievement Awards, with a brief historical overview. Workshops will be designed to be interactive rather than shorter plenary-type talks.